tbuckley/cabot-search huggingface dataset:
Abstract 4531: Clinical translation of biomarkers for ZL-1211, an anti-CLDN18.2 antibody, in patients with advanced solid tumors from a phase I dose-escalation study
Authors: Zhen Luo, Xiao Wang, Xuehuo Zeng, Jiaqing Yi, Tegan Burns, Herman Liu, Xinyu Zhang, Wenyu Liu, Karl Hsu, Hua Gong
Journal: Cancer Research (2023)

Abstract ZL-1211, a humanized monoclonal IgG1 antibody targeting CLDN18.2, induces cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). We developed ex vivo ADCC and CDC assays to study the mechanism of actions of ZL-1211. Our preclinical data has demonstrated greater antitumor activities than the clinical leading benchmark via enhanced ADCC by mutation in Fcγ domain and potent CDC activities. We used those ex vivo assays to further profile the clinical specimens from patients collected at baseline (pre-infusion) and the following cycles (post-infusion) in our phase 1 study (NCT05065710). Preliminary results in clinical samples indicated that baseline ADCC and CDC capabilities were correlated with anti-tumor activity of ZL-1211 in patients with CLDN18.2-positive locally advanced or metastatic solid tumors, suggesting probable predictive biomarkers. Results also showed that changes in circulating ZL-1211 mediated ADCC and CDC activities were dose-dependent and in accordance with the pharmacokinetic (PK) profile. In addition, we performed differential gene expression analysis and real-time PCR to compare gene expression in ZL-1211 responder and non-responder PDX models and CCLE cell lines. Our findings reveal that several immune-related genes may serve to predict the responses to ZL-1211 treatment. Other potential predictive biomarkers such as Fcγ receptor CD16A polymorphism and baseline stromal CD8 expression were also evaluated in clinical samples. Taken together, analytical approaches developed and validated from preclinical studies were successfully translated to characterize clinical samples in the current Phase 1 trial. The exploratory analysis indicated the clinical relevance of multiple biomarkers and their potential as predictive biomarkers of ZL-1211. Citation Format: Zhen Luo, Xiao Wang, Xuehuo Zeng, Jiaqing Yi, Tegan Burns, Herman Liu, Xinyu Zhang, Wenyu Liu, Karl Hsu, Hua Gong. Clinical translation of biomarkers for ZL-1211, an anti-CLDN18.2 antibody, in patients with advanced solid tumors from a phase I dose-escalation study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4531.
Abstract 494: BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors
Authors: Pingping Wang, Rongwen Yang, Yun Sun, Xuepeng Ju, Jiayu Zhao, Yanju Liu, Xiaoyun Liu, Zhengyao Zou, Jialin Ren, Min Wang, Haibo Chen, Xuegang Yi, Jian Zhang, Teng Ma, Gaoliang Cheng, Lijia Liu, Jing Guo, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2023)

Abstract The most observed alteration in clear cell renal cell carcinoma (ccRCC) is the inactivation of the tumor suppressor von Hippel-Lindau (VHL) E3 ligase due to genetic predisposition, somatic mutations, or methylation. Loss of VHL can lead to hypoxia-inducible factor 2α (HIF-2α) accumulation and elevated expression of HIF target genes, such as VEGFA, many of which facilitate angiogenesis, proliferation, and metastasis of ccRCC. Therefore, inhibiting HIF-2α has become a new strategy for the treatment of ccRCC. Here, we present the discovery of BPI-452080, a selective small molecule HIF-2α inhibitor. In VHL defective ccRCC cell lines, BPI-452080 potently and selectively blocked the heterodimerization of HIF-2α with HIF-1β, but not that of HIF-1α with HIF-1β. It inhibited the downstream hypoxia-responsive gene transcription and VEGFA protein secretion. In multiple xenograft mouse models, oral administration of BPI-452080 significantly inhibited tumor growth in a dose-dependent manner. BPI-452080 demonstrated good PK/PD correlation in the 786-O xenograft model after a single dosing, as shown by a concentration-dependent inhibition of VEGFA secretion in plasma and a reduction of the mRNA levels of VEGFA, CXCR4, CCND1, and GLUT1 genes in tumor tissue. Moreover, BPI-452080 exhibited good bioavailability in multiple pre-clinical species, favorable ADME properties, and good tolerance in toxicology studies. In conclusion, BPI-452080 is a potent, selective, and orally bioavailable HIF-2α inhibitor which presents a novel therapeutic option for ccRCC, von Hippel-Lindau disease, and other solid tumors. BPI-452080 is planned to enter Phase I clinical trial in China in early 2023. Citation Format: Pingping Wang, Rongwen Yang, Yun Sun, Xuepeng Ju, Jiayu Zhao, Yanju Liu, Xiaoyun Liu, Zhengyao Zou, Jialin Ren, Min Wang, Haibo Chen, Xuegang Yi, Jian Zhang, Teng Ma, Gaoliang Cheng, Lijia Liu, Jing Guo, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 494.
Abstract 471: A new synthetic peptide DS-2 enhanced anti-tumor activity by targeting human telomerase reverse transcriptase (hTERT) in prostate cancer cells
Authors: Jae Hyeon Park, Joo Kyung Shin, Joo Hee Han, Hyung Sik Kim
Journal: Cancer Research (2023)

Abstract Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers. Therefore, hTERT is considered as an important target for cancer therapy. In the present study, we synthetized a new peptide, DS-2, based on the telomerase vaccine GV1001, a 16-mer peptide. The aim of this study is to evaluate the molecular mechanism of DS-2 on the anticancer activity by targeting hTERT in prostate cancer cells. The expression levels of hTERT in prostate cancer patients were measured. We compared the cytotoxic activity of GV1001 and DS-2 against different prostate cancer cell lines. Flow cytometry was used to evaluate the effects of DS-2 on apoptosis. The scratch-wound assay and matrigel invasion assay were performed to determine the metastasis ability of prostate cancer cells. We further measured the telomerase enzyme activity of DS-2 in LNCaP cells. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of GV1001 and DS-2. The cytotoxicity of human peripheral blood mononuclear cells (PBMC) on prostate cancer cells was determined by lactate-dehydrogenase (LDH)-release assay. The hTERT expression was directly correlated with telomerase activity in LNCaP cells, and DS-2 significantly inhibited telomerase enzyme activity, resulting in reducing LNCaP cells proliferation and metastasis. Furthermore, DS-2 exhibited the most substantial anti-cancer potential against prostate cancer cells compared with different cancer cell lines. In the tumor-bearing nude mice model, DS-2 significantly inhibited the growth of the prostate tumor and downregulated the expression of hTERT and Ki-67 in the tumor tissue as evidenced by western blot and immunohistochemistry analysis, respectively. Furthermore, the potent cytotoxicity was exhibited in LNCaP cells after treated with DS-2-activated PBMC plus IL-2. In addition, DS-2 synergistically enhanced IL-2 production from activated PBMC. These data indicated that the inhibition of hTERT expression by DS-2 suppressed prostate cancer cell growth and induced anti-cancer immunity. Therefore, DS-2 might be used as a novel therapeutic drug for cancer immunotherapy by targeting hTERT in prostate cancer. Citation Format: Jae Hyeon Park, Joo Kyung Shin, Joo Hee Han, Hyung Sik Kim. A new synthetic peptide DS-2 enhanced anti-tumor activity by targeting human telomerase reverse transcriptase (hTERT) in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 471.
Abstract 1657: Discovery of a first-in-class multifunctional TYMS non-classical antifolate inhibitors with potent <i>in vivo</i> activity that prolongs survival
Authors: Peter Elias Dib, Maria Guijarro, Patrick Kellish, Nick Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Derek Leas, Nick Borrero, Carlos Modenutti, Richard Bennett, Jonathan Licht, Robert McKenna, Adrian Roitberg, Frederic Kaye, Maria Zajac-Kaye
Journal: Cancer Research (2023)

Abstract Thymidylate synthase (TYMS/TS) is overexpressed in many cancer types and is commonly associated with advanced disease. TYMS catalyzes the de novo synthesis reaction of deoxythymidine monophosphate (dTMP), one of the building blocks of DNA. Although TYMS inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance limiting overall benefit. Here we report a small molecule TYMS inhibitor and its two analogues that exhibit i) enhanced anti-tumor activity as compared to current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) are structurally distinct from classical antifolates, iii) extend survival in both pancreatic xenograft tumor models and hTS/Ink4a/Arf null genetically engineered mouse tumor model, iv) and are well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we confirm the compound and its analogues are a multifunctional non-classical antifolate, and we identify structural features allowing direct TYMS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non-classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy. Citation Format: Peter Elias Dib, Maria Guijarro, Patrick Kellish, Nick Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Derek Leas, Nick Borrero, Carlos Modenutti, Richard Bennett, Jonathan Licht, Robert McKenna, Adrian Roitberg, Frederic Kaye, Maria Zajac-Kaye. Discovery of a first-in-class multifunctional TYMS non-classical antifolate inhibitors with potent in vivo activity that prolongs survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1657.
Abstract 6516: Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice
Authors: Tarek Bacha, Natalia Cortez Penso, Maria Rodriguez, Brian Hong, Gerardo Mackenzie
Journal: Cancer Research (2023)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) remains among the most lethal cancers. PDAC can take up to 15-20 years to develop from the occurrence of the first initiating mutational event, which opens the opportunity for intervention and prevention strategies. In particular, nutritional interventions could provide an avenue to prevent or slow down pancreatic carcinogenesis, since certain diets such as high-fat diets (HFD) have shown to promote it. On the other hand, ketogenic diets (KD), characterized by a high fat and very low carbohydrate content, have gained attention for their anti-tumor and anti-inflammatory potential. However, the role of a KD in the onset and progression of PDAC is still unknown. In this project, we investigated the impact of both a HFD and a KD on late-stage pancreatic carcinogenesis. For this purpose, we used an animal model of pancreatic cancer carrying a pancreas-specific oncogenic KRASG12D mutation [LSL-KRASG12D; P48+/Cre; (KC mice)]. On average, KC mice develop PDAC at 12-15 months of age, so they are a valuable tool to study late-stage carcinogenesis. We hypothesized that a HFD would accelerate PDAC progression while a KD would slow it down. To test our hypothesis, 6 months-old male and female KC mice (n=18/group) were randomized and fed, either a control diet (CD), a HFD, or a KD for 6 months and then euthanized at 12-months of age to evaluate pancreatic cancer incidence and progression. At 12-months of age, HFD-fed mice had significantly higher body weight compared to the other two groups. Moreover, KD-fed mice had significantly higher levels of blood ketone bodies, with lower levels of glucose and serum insulin levels, when compared to KC mice fed a HFD. However, after 6 months on the diets, no significant differences in pancreas weight nor in PDAC incidence were observed across all diet groups. Of note, male KC mice experienced double the PDAC incidence rates (55%) than female KC mice (27%), irrespectively of the group. In addition, no significant differences among the groups were observed in RAS/RAF/ERK and PI3K/AKT/mTOR pathways, known to be associated with cancer proliferation. In summary, despite the improvement in insulin and increases in ketone bodies, consumption of a strict KD failed to improve late-stage pancreatic carcinogenesis in mice. Citation Format: Tarek Bacha, Natalia Cortez Penso, Maria Rodriguez, Brian Hong, Gerardo Mackenzie. Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6516.
Abstract 562: Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer
Authors: Kristopher A. Lofgren, Sreeja Sreekumar, Paraic A. Kenny
Journal: Cancer Research (2023)

Abstract The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we describe the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. A pan-cancer tissue microarray analysis indicates that the target is commonly detected (&amp;gt; 50% of cases) in breast, prostate, liver and lung cancer. Citation Format: Kristopher A. Lofgren, Sreeja Sreekumar, Paraic A. Kenny. Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 562.
Abstract 2409: A synergistic effect of miR-21-5p inhibitor and PARP1 inhibitor to enhance the radiosensitivity of oral squamous cell carcinoma
Authors: Lin Ma, Weitao Hu, Rui Fu, Anhui Wu, Qiangyong Deng, Qi Liu
Journal: Cancer Research (2023)

Abstract Radiotherapy is one of the standard treatments for oral squamous cell carcinoma (OSCC). Radiotherapy damages cancer cells mainly by inducing DNA double-strand breaks, but some advanced OSCC can effectively repair DNA damages, resulting in radiotherapy resistance. TCGA data showed that miR-21-5p was highly expressed in advanced OSCC and correlated with prognosis. However, the involvement of miR-21-5p in OSCC’s response to radiotherapy and the underlying mechanism are still unclear. When treated with a miR-21-5p inhibitor, we found OSCC cell lines (SAS and CAL33) became more sensitive to X-ray radiation at 2Gy (the commonly used single-dose in conventional radiotherapy), which was supported by the evidence that more resident 53BP1-marked-foci for non-repaired DNA double strand breaks (1.61±0.54 folder more in SAS, 1.47±0.49 folder more in CAL33, n=4, p&amp;lt;0.05) and less colony-forming capacity (14.62±2.36% in SAS, 18.65±4.32% in CAL33, n=3, p&amp;lt;0.05) than untreated control cells were observed at 24hr after radiation. However, the expression of PARP1, a DNA damage sensor for recognizing DNA damage and facilitating DNA repair, was significantly increased (1.38±0.12, n=4, p&amp;lt;0.05) in SAS cells treated with miR-21-5p inhibitor. In order to achieve a better tumor control, we tested the combined treatments with miR-21-5p inhibitor and PARP1 inhibitor (Olaparib) on SAS cells, which resulted in a synergistic effect in inhibition of the repair of DNA double strand breaks. The residual 53BP1 foci after 2Gy X-ray irradiation was increased 1.45±0.06 folder more when inhibiting both miR-21-5p and PARP1, while the colony-forming capacity of irradiated SAS cells was decreased by 39.55±5.89% (p&amp;lt;0.0001) in the same conditions. This work provided novel insights on the molecular mechanism of miR-21-5p regulated cell response to radiotherapy, which may give rise to potential therapeutic strategy for treatment of advanced OSCC. Citation Format: Lin Ma, Weitao Hu, Rui Fu, Anhui Wu, Qiangyong Deng, Qi Liu. A synergistic effect of miR-21-5p inhibitor and PARP1 inhibitor to enhance the radiosensitivity of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2409.
Abstract 2546: Targeting of AKT/β-catenin signaling pathways driven hepatocellular carcinoma cell lines by combined treatment of HDAC and multi-kinase inhibitors
Authors: Mohamed Mahmoud Elberawi, Mohamed Abdulqadir, Ahmed Samir Sultan
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is the dominant type of liver cancer exhibiting high mortality and poor prognosis with the fastest rate of death due to its aggressiveness and lack of effective therapies. Beta-catenin is a key player transcriptional factor, which orchestrates gene expression in HCC progression. Activation of β-catenin is promoted by its phosphorylation by AKT. Although the studies of metastatic behavior of β-catenin over-expressing HCC cells are not clear, the present study is focusing on the relationship between chromatin remodelling through deacetylation and phosphorylation of β-catenin by AKT. The current study investigated the role of a combination of Lenvatinib, a multi-kinase inhibitor, and Belinostat, a histone deacetylase inhibitor (HDACI), on two HCC cell lines, Hep G2 and Hep 3B, respectively. In-depth, our data showed that combined treatment significantly induced morphological changes in the tested cell lines with activation of caspase-3 and pre-apoptotic signals of Bcl-2, Bcl-XL, and Bax, indicating apoptotic induction after 48 hours of treatment compared to the control or each drug separately. The calculated IC50 was 1µmol/L for Belinostat and 25 n mole/L for Lenvatinib. Western blotting analysis reveals that the combined treatment for 48 hours inhibited the oncogenic β-catenin, AKT, and TGFβ expression in a dose-dependent manner.In addition, the combined treatment inhibited the localization of beta-catenin in the tested cell nuclei after 48 hours as confirmed by IHC staining. Statistical analysis proved that the combination of both drugs significantly decreased the proliferation and invasion of both cell lines (P&amp;lt;0.01, ANOVA) compared to each drug alone. In addition, the percentage of apoptotic cells was significantly increased and showed a cell cycle arrest in the G0/G1 phase of Hep-G2 cells after 48 hours of combined treatment as confirmed by flow cytometry. All in all, our data show that targeting AKT/β-catenin driven HCC progression can be targeted by Lenvatinib and Belinostat combined treatment. Citation Format: Mohamed Mahmoud Elberawi, Mohamed Abdulqadir, Ahmed Samir Sultan. Targeting of AKT/β-catenin signaling pathways driven hepatocellular carcinoma cell lines by combined treatment of HDAC and multi-kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2546.